DESCRIPTION (provided by investigator): Immunological memory is critical to adaptive immunity. In the periphery, some cells can recognize self-antigen and memory development must be prevented. To understand how to generate vigorous recall responses while protecting against autoimmunity, it is essential to determine activation differences between naive and memory cells. A key question concerns how some stimuli activate cells while others induce tolerance. This is especially pertinent to memory, as memory cells are hypo-responsive or tolerant to certain agents (eg. superantigens and anti-CD3 Abs) that are strong stimulants of naive cells. This dichotomy provides strong evidence that naive and memory cells use different means to achieve a balance between immunity and tolerance. The objective of this proposal is to determine how superantigens induce tolerance in memory T cells and to better understand how improper activation of memory cells use is prevented. Thus, the planned studies will determine the activation paths of CD4 memory T cells in response to peptide antigen and superantigens. Since both antigens and superantigens may be normally encountered, understanding how they differently impact the immune system has important implications for pathology and therapy. A TCR transgenic mouse model will be used to obtain naive and memory cells bearing receptors that bind to the same peptide antigen and the same superantigen. This model will be used to test the hypothesis that superantigen induces tolerance selectively in memory T cells because of signal transduction differences in naive and memory cells. The specific aims are: 1) to identify unique signaling properties in memory T cells exposed to SEB; 2) to determine if exposure of memory cells to superantigen potentiates inhibition by negative regulators of TCR/CD3 signaling; and, 3) to determine the organizational structure of signaling proteins within the membrane of memory cells before and after exposure to superantigen. The sum of these studies will contribute to our understanding of changes occurring during the differentiation of naive cells into memory cells, will provide information on how bacterial superantigens may modulate immunity during infection, and will aid in the development of cell-specific therapies for autoimmune disease.